CN110291081B - Benzimidazole compounds as C-KIT inhibitors - Google Patents

Benzimidazole compounds as C-KIT inhibitors Download PDF

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CN110291081B
CN110291081B CN201780085539.3A CN201780085539A CN110291081B CN 110291081 B CN110291081 B CN 110291081B CN 201780085539 A CN201780085539 A CN 201780085539A CN 110291081 B CN110291081 B CN 110291081B
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methyl
imidazol
benzo
ethynyl
trifluoromethyl
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CN110291081A (en
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尼古拉斯·E·本西文加
戴维·C·达尔加诺
约瑟夫·M·戈兹吉特
黄卫生
安娜·科尔曼
李锋
齐绩伟
威廉·C·莎士比亚
兰尼·M·托马斯
王义汉
张蕴
朱笑天
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Ariad Pharmaceuticals Inc
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Abstract

The present invention relates to c-Kit inhibitors useful for the treatment of cancer and other serine-threonine kinase-mediated diseases, said inhibitors having the formula:
Figure DDA0002153914870000011
of which A, L, R 1 、R 2 、R 3 And n is as described herein.

Description

Benzimidazole compounds as C-KIT inhibitors
Cross Reference to Related Applications
This application claims priority to U.S. provisional patent application serial No. 62/434,839, filed 2016, 12, 15, the entire contents of which are hereby incorporated by reference.
Technical Field
The present invention relates to inhibitors of the tyrosine-protein kinase Kit (c-Kit) useful for the treatment of diseases or disorders associated with c-Kit. In particular, the invention relates to compounds and compositions that inhibit c-Kit, methods of treating diseases or conditions associated with c-Kit, and methods of synthesizing these compounds.
Background
The discovery and introduction of the Tyrosine Kinase Inhibitor (TKI) imatinib (imatinib) as a treatment to inhibit Kit has changed the clinical management of gastrointestinal stromal tumors (GIST) (colless, c.l. et al, nat. Rev. Cancer 2011 11. Nevertheless, most imatinib-treated patients eventually relapse due to the growth of clones with secondary, drug-resistant KIT mutations (Heinrich, m.c. et al, j.clin.oncol.2006;24 4764-74. Secondary mutations typically occur in the ATP-binding pocket encoded by exons 13 and 14, as well as in the activation loop (a-loop) encoded by exons 17 and 18. The challenge of treating imatinib-resistant GIST is complicated by mutation heterogeneity, as patients can harbor a variety of different secondary mutations in different tumor lesions or even in different regions of the same lesion (Wardelmann e. et al, clin. Cancer res.2006; 12.
GIST patients with imatinib-resistant tumors were treated with sunitinib, which potently inhibits the KIT ATP-pocket mutant (Heinrich, m.c. et al, J Clin Oncol 2008. However, sunitinib was not effective against the a-loop mutant, which accounted for 50% of the imatinib-resistant mutations. This may explain why the Overall Response Rate (ORR) is low (7%) and the median progression-free survival (PFS) is short (6.2 months) (demeri, g.d. et al, lancet 2006, 1329-38. Regorafenib was recently approved as a three-line therapy, but also showed only moderate activity, with an ORR of 4.5% and median PFS of 4.8 months (demmetri, g.d. et al, lancet 2013. Regorafenib has not been extensively analyzed for Kit inhibitory properties, but both clinical and initial preclinical data indicate a limited spectrum of sensitive Kit mutants (George, s. Et al, j.clin.oncol.2012,30 2401-7, serrano-Garcia, c. Et al, ASCO recording abs 2013 (15. Suppl): 10510). Therefore, additional agents are needed to overcome resistance mutations in KIT, especially in the a-loop.
The Kit inhibitors imatinib, sunitinib and regorafenib are effective GIST therapies, but most patients develop resistance to these drugs due to the polyclonal secondary Kit mutants obtained from somatic cells. The lack of efficacy of any single agent for the entire set of potential ATP-binding pocket and a-loop secondary mutants makes long-term overall disease control challenging in advanced patients. To address this unmet medical need, compounds are provided herein that target a wide range of primary and secondary Kit mutants, including mutants within the a-loop.
Disclosure of Invention
The present disclosure provides novel benzimidazole compounds and pharmaceutically acceptable salts as potent c-Kit inhibitors.
The first aspect of the present invention relates to compounds of formula (I):
Figure GDA0003427688590000021
and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers thereof,
wherein:
l is-C (O) NR 5 -or-NR 5 C(O)-；
A is (C) 6 -C 10 ) Aryl or 5 to 10 membered heteroaryl, wherein said aryl or heteroaryl is interrupted by one or more R 4 Optionally substituted;
R 1 is H, (C) 1 -C 6 ) Alkylamino or (C) 1 -C 6 ) A dialkylamino group;
R 2 is H, (C) 1 -C 6 ) Alkyl, - (C (R) 6a ) 2 ) p -(C 3 -C 7 ) Cycloalkyl, - (C (R) 6a ) 2 ) p -heterocycloalkyl, wherein said heterocycloalkyl comprises 4 to 7 membered rings and 1 to 3 heteroatoms selected from N, O and S, - (C (R) 6a ) 2 ) p -(C 6 -C 10 ) Aryl or- (C (R) 6a ) 2 ) p -heteroaryl, wherein said heteroaryl comprises a 5 or 6 membered ring and 1 to 3 heteroatoms selected from N, O and S, wherein said aryl is interrupted by one or more R 7 Optionally substituted, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted with one or more R 9 Optionally substituted;
each R 3 Independently at each occurrence is (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkoxy group, (C) 1 -C 6 ) Haloalkyl, (C) 1 -C 6 ) Haloalkoxy, halogen or OH;
each R 4 Independently at each occurrence is (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) An alkoxy group(s),
(C 1 -C 6 ) Haloalkyl, (C) 1 -C 6 ) Haloalkoxy, halogen, -OH, CN, (C) 3 -C 7 ) Cycloalkyl, - (C (R) 6b ) 2 ) q -NH 2 、-(C(R 6b ) 2 ) q -(C 1 -C 6 ) Alkylamino, - (C (R) 6b ) 2 ) q -(C 1 -C 6 ) A dialkylamino group, or a dialkylamino group,
-(C(R 6b ) 2 ) q -heterocyclic ringAlkyl, wherein the heterocycloalkyl contains 4 to 7 membered rings and 1 to 3 heteroatoms selected from N, O and S, or — (C (R) 6b ) 2 ) q -heteroaryl, wherein said heteroaryl comprises a 5 or 6 membered ring and 1 to 3 heteroatoms selected from N, O and S, and wherein said heterocycloalkyl or said heteroaryl is optionally substituted with one or more substituents each independently selected from (C) 1 -C 6 ) Alkyl, -NH 2 、(C 1 -C 6 ) Alkylamino and (C) 1 -C 6 ) A dialkylamino group;
R 5 is H, (C) 1 -C 6 ) Alkyl or (C) 1 -C 6 ) A haloalkyl group;
each R 6a And R 6b Independently is H or (C) 1 -C 6 ) An alkyl group;
R 7 is (C) 1 -C 6 ) Alkoxy group, (C) 1 -C 6 ) Haloalkoxy, -OH, -NH 2 、(C 1 -C 6 ) Alkylamino radical, (C) 1 -C 6 ) Dialkylamino or-C (O) N (R) 8 ) 2 ；
Each R 8 Independently H, (C) 1 -C 6 ) Alkyl or (C) 1 -C 6 ) A haloalkyl group;
each R 9 Independently at each occurrence is (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Haloalkyl, -C (O) H, -C (O) (C) 1 -C 6 ) An alkyl or 5 to 7 membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from N, O and S, wherein said heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C) 1 -C 6 ) Alkyl, -C (O) H or
-C(O)(C 1 -C 6 ) And wherein said aryl is optionally substituted with one or more substituents each independently selected from (C) 1 -C 6 ) Alkoxy, -OH, (C) 1 -C 6 ) Haloalkoxy, -NH 2 、(C 1 -C 6 ) Alkylamino or (C) 1 -C 6 ) A dialkylamino group; and is provided with
Each n, p and q is independently 0, 1 or 2.
A second aspect of the invention relates to a method of treating a c-Kit mediated disease or condition. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
Another aspect of the invention relates to a method of preventing a c-Kit mediated disease or condition. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
Another aspect of the invention relates to methods of inhibiting c-Kit. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
Another aspect of the invention relates to methods of treating diseases or disorders associated with the inhibition of c-Kit. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
Another aspect of the invention relates to methods of preventing diseases or disorders associated with the inhibition of c-Kit. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
Another aspect of the invention relates to a method of treating cancer. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
Another aspect of the invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may also include excipients, diluents or surfactants.
Another aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for the treatment of a disease associated with the inhibition of c-Kit.
Another aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, for use in the manufacture of a medicament for the prevention of diseases associated with the inhibition of c-Kit.
Another aspect of the invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease associated with the inhibition of c-Kit.
Another aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for the prevention of a disease associated with the inhibition of c-Kit.
The present invention also provides methods of treating or preventing diseases or disorders associated with the modulation of c-Kit, including cancer and cell proliferative disorders, multiple sclerosis, asthma, inflammatory disorders, allergic reactions, fibrotic disorders and metabolic disorders, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.
The present invention provides inhibitors of c-Kit that are therapeutic agents for the treatment of diseases such as cancer and cell proliferative disorders, multiple sclerosis, asthma, inflammatory disorders, allergic reactions, fibrotic disorders and metabolic disorders.
The present disclosure provides agents having novel mechanisms of action on the c-Kit enzyme in the treatment of various types of diseases, including cancer and cell proliferative disorders, multiple sclerosis, asthma, mastocytosis, inflammatory disorders, allergic reactions, fibrotic disorders, autoimmune pathogenesis, and metabolic disorders. Finally, the present invention provides the medical community with novel pharmacological strategies for the treatment of c-Kit related diseases and disorders.
Detailed Description
The present invention relates to compounds and compositions capable of inhibiting c-Kit activity. The invention features a method of treating, preventing, or ameliorating a disease or disorder in which c-Kit plays a role by administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. The methods of the invention are useful for treating a variety of c-Kit dependent diseases and disorders by inhibiting the activity of the c-Kit enzyme. Inhibition of c-Kit provides novel methods for treating, preventing or ameliorating diseases, including but not limited to cancer and metastatic disease.
In a first aspect of the invention, compounds of formula (I) are described:
Figure GDA0003427688590000051
and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers thereof, wherein A, L, R 1 、R 2 、R 3 And n is as described above.
The details of the invention are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited in this specification are herein incorporated by reference in their entirety.
Definition of
The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.
The term "and/or" is used in this disclosure to mean "and" or "unless otherwise indicated.
The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., alkyl) may, but need not, be bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have a substituent other than hydrogen. For example, it may be bonded at any position along the chain to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any other functional groups. Suitable substituents for optionally substituting the desired group include, but are not limited to, halogen, oxo, -OH, -CN, -COOH, -CH 2 CN、-O-(C 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkoxy group, (C) 1 -C 6 ) Haloalkyl, (C) 1 -C 6 ) Haloalkoxy, -O- (C) 2 -C 6 ) Alkenyl, -O- (C) 2 -C 6 ) Alkynyl, (C) 2 -C 6 ) Alkenyl, (C) 2 -C 6 ) Alkynyl, -OH, -OP (O) (OH) 2 、-OC(O)(C 1 -C 6 ) Alkyl, -C (O) (C) 1 -C 6 ) Alkyl, -OC (O) O (C) 1 -C 6 ) Alkyl, -NH 2 、-NH((C 1 -C 6 ) Alkyl), -N ((C) 1 -C 6 ) Alkyl radical) 2 、-NHC(O)(C 1 -C 6 ) Alkyl, -C (O) NH (C) 1 -C 6 ) Alkyl, -S (O) 2 (C 1 -C 6 ) Alkyl, -S (O) NH (C) 1 -C 6 ) Alkyl and S (O) N ((C) 1 -C 6 ) Alkyl radical) 2 . Substituent groupMay itself be optionally substituted. As used herein, "optionally substituted" also refers to substituted or unsubstituted, the meaning of which is set forth below.
As used herein, the term "substituted" means that the specified group or moiety bears one or more suitable substituents, wherein the substituents may be attached to the specified group or moiety at one or more positions. For example, cycloalkyl-substituted aryl may mean that the cycloalkyl is attached to one atom of the aryl group by a bond or to the aryl group by being fused to the aryl group and sharing two or more common atoms.
Unless otherwise specifically stated, the term "aryl" refers to a cyclic, aromatic hydrocarbon group having from 1 to 3 aromatic rings, including monocyclic or bicyclic groups, such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be linked at one point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted at any point of attachment with one or more substituents, for example 1-5 substituents. Exemplary substituents include, but are not limited to, -H, -halo, O- (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkyl, -O- (C) 2 -C 6 ) Alkenyl, -O- (C) 2 -C 6 ) Alkynyl, (C) 2 -C 6 ) Alkenyl, (C) 2 -C 6 ) Alkynyl, -OH, -OP (O) (OH) 2 、-OC(O)(C 1 -C 6 ) Alkyl, -C (O) (C) 1 -C 6 ) Alkyl, -OC (O) O (C) 1 -C 6 ) Alkyl, NH 2 、NH((C 1 -C 6 ) Alkyl), N ((C) 1 -C 6 ) Alkyl radical) 2 、-S(O) 2 -(C 1 -C 6 ) Alkyl, -S (O) NH (C) 1 -C 6 ) Alkyl and S (O) N ((C) 1 -C 6 ) Alkyl radical) 2 . The substituents themselves may be optionally substituted. Further, when containing two fused rings, aryl groups as defined herein may have an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems for these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalkenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydrobenzrenyl, and the like.
Unless otherwise specifically defined, "heteroaryl" means a monovalent monocyclic aromatic group or polycyclic aromatic group of 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O or S, the remaining ring atoms being C. Heteroaryl as defined herein also refers to bicyclic heteroaromatic groups wherein the heteroatom is selected from N, O or S. The aromatic groups are independently optionally substituted with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno [3,2-b]Thiophene, triazolyl, triazinyl, imidazo [1,2-b]Pyrazolyl, furo [2,3-c]Pyridyl, imidazo [1,2-a]Pyridyl, indazolyl, pyrrolo [2,3-c]Pyridyl, pyrrolo [3,2-c]Pyridyl, pyrazolo [3,4-c]Pyridyl, thieno [3,2-c]Pyridyl, thieno [2,3-c]Pyridyl, thieno [2,3-b]Pyridyl, benzothiazolyl, indolyl, indolinyl, indolonyl, dihydrobenzothienyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazinyl, dihydrobenzoxazinyl (dihydrobenzoxanyl), quinolinyl, isoquinolinyl, 1,6-naphthyridine, benzo [ de ] de]Isoquinolinyl, pyrido [4,3-b][1,6]Naphthyridinyl, thieno [2,3-b]Pyrazinyl, quinazolinyl, tetrazolo [1,5-a]Pyridyl, [1,2,4]Triazolo [4,3-a]Pyridyl, isoindolyl, pyrrolo [2,3-b]Pyridyl, pyrrolo [3,4-b]Pyridyl, pyrrolo [3,2-b]Pyridyl, imidazo [5,4-b]Pyridyl, pyrrolo [1,2-a]Pyrimidinyl, tetrahydropyrrolo [1,2-a]Pyrimidinyl, 3,4-dihydro-2H-1 Lambda 2 -pyrrolo [2,1-b]Pyrimidine, dibenzo [ b, d ]]Thiophene, pyridine-2-one, furo [3,2-c]Pyridyl, furo [2,3-c]Pyridyl, 1H-pyridyl [3,4-b][1,4]Thiazinyl, benzoxazolyl, benzisoxazolyl, furo [2,3-b]Pyridyl, benzothienyl, 1,5-naphthyridinyl, furo [3,2-b]Pyridine, [1,2,4]Triazolo [1,5-a]Pyridyl, benzo [1,2,3]Triazolyl, imidazo [1,2-a]Pyrimidinyl, [1,2,4]Triazolo compounds[4,3-b]Pyridazinyl, benzo [ c)][1,2,5]Thiadiazolyl, benzo [ c ]][1,2,5]Oxadiazole, 1,3-dihydro-2H-benzo [ d]Imidazol-2-one, 3,4-dihydro-2H-pyrazolo [1,5-b][1,2]Oxazinyl, 4,5,6,7-tetrahydropyrazolo [1,5-a]Pyridyl, thiazolo [5,4-d]Thiazolyl, imidazo [2,1-b][1,3,4]Thiadiazolyl, thieno [2,3-b]Pyrrolyl, 3H-indolyl and derivatives thereof. Further, when containing two fused rings, aryl groups as defined herein may have an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems for these heteroaryl groups include indolinyl, indolonyl, dihydrobenzothienyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl and dihydrobenzoxazinyl.
Halogen or "halo" refers to fluorine, chlorine, bromine or iodine.
Alkyl refers to straight or branched chain saturated hydrocarbons containing 1 to 12 carbon atoms. (C) 1 -C 6 ) Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
"alkoxy" means a straight or branched chain saturated hydrocarbon containing from 1 to 12 carbon atoms and having a terminal "O" in the chain, i.e., -O (alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy.
"alkenyl" means a straight or branched chain unsaturated hydrocarbon containing from 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. The double bond of the alkenyl group may be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, isobutenyl, pentenyl or hexenyl. Alkenyl groups may be unsubstituted or substituted. As defined herein, an alkenyl group can be straight or branched.
"alkynyl" means a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. "alkynyl" groups contain at least one triple bond in the chain. Examples of alkynyl include ethynyl, propynyl, n-butynyl, isobutynyl, pentynyl or hexynyl. Alkynyl groups may be unsubstituted or substituted.
"cycloalkyl" means a monocyclic saturated carbocyclic ring containing 3 to 18 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl (norbomenyl), norbornenyl (norbomenyl), bicyclo [2.2.2] octyl, or bicyclo [2.2.2] octenyl.
A "heterocyclyl" or "heterocycloalkyl" monocyclic ring contains carbon and heteroatoms selected from oxygen, nitrogen or sulfur, and wherein there is no delocalized electron pi (aromaticity) shared between ring carbons or heteroatoms. The heterocycloalkyl ring structure may be substituted with one or more substituents. The substituents themselves may be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxanyl, piperidinyl, morpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl (tropanyl), oxazolidinone (oxzolidinonyl), and Gao Tuowan (homotropanyl).
The term "hydroxyalkyl" means an alkyl group as defined above wherein the alkyl group is substituted with one or more-OH groups. Examples of hydroxyalkyl radicals include HO-CH 2 -、HO-CH 2 -CH 2 -and CH 3 -CH(OH)-。
The term "haloalkyl" as used herein refers to an alkyl group, as defined herein, substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like.
The term "haloalkoxy" as used herein refers to an alkoxy group, as defined herein, substituted with one or more halogens. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, and the like.
The term "amine" as used herein refers to a primary amine (R-NH) 2 R.noteq.H), secondary amines (R) 2 -NH，R 2 Not equal to H) and tertiary amines (R) 3 -N, R ≠ H). Substituted amine is intended to mean an amine in which at least one hydrogen atom has been replaced by a substituent.
The term "amino" as used herein means a substituent containing at least one nitrogen atom. Specifically, the term "amino" includes NH 2 -NH (alkyl) or alkylamino, -N (alkyl) 2 Or dialkylamino, amide-, carboxamide-, urea and sulfonamide substituents.
The term "alkylamino" as used herein refers to an amino group or NH wherein one hydrogen has been substituted by an alkyl group as defined above 2 A group, i.e., -NH (alkyl). Examples of alkylamino include, but are not limited to, methylamino (i.e., -NH (CH) 3 ) Ethyl amino group, propyl amino group, isopropyl amino group, n-butyl amino group, sec-butyl amino group, tert-butyl amino group, etc.
The term "dialkylamino" as used herein refers to an amino or NH wherein both hydrogens have been substituted with an alkyl group as defined above 2 Radical, i.e. -N (alkyl) 2 . The alkyl groups on the amino groups may be the same or different alkyl groups. Examples of alkylamino include, but are not limited to, dimethylamino (i.e., -N (CH) 3 ) 2 ) Diethylamino, dipropylamino, diisopropylamino, di-n-butylamino, di-sec-butylamino, di-tert-butylamino, methyl (ethyl) amino, methyl (butylamino) and the like.
The term "oxo" as used herein refers to a "= O" group.
The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. Such solvents for the purposes of the present invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, meOH, etOH, and AcOH. Solvates in which water is the solvent molecule are commonly referred to as hydrates. Hydrates include compositions containing a stoichiometric amount of water, as well as compositions containing variable amounts of water.
The term "isomers" refers to compounds having the same composition and molecular weight but differing in physical and/or chemical properties. The structural differences may be structural (geometric isomers) or the ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, the compounds of formula (I) may have one or more asymmetric carbon atoms and may exist as racemates, racemic mixtures and individual enantiomeric or diastereomeric forms.
The disclosure also includes pharmaceutical compositions comprising an effective amount of the disclosed compounds and a pharmaceutically acceptable carrier. <xnotran> " " , , , (amsonate) (3236 zxft 3236- -5262 zxft 5262- ), , , , , , , , , , , (camsylate), , , , (clavulariate), , , (edisylate), (estolate), (esylate), (fumerate), (fiunarate), , , , (glycollylarsanilate), , (hexylresorcinate), , , , , , , , , , , , , , , , , , , , , N- ,3- -2- , , , , (3763 zxft 3763- - -2- -3- , (einbonate)), , / , , , </xnotran> Propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suraminate (sulfamate), tannate, tartrate, 8-chlorotheophylline (teoclate), toluenesulfonate, triethyliodide and valerate.
A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey.
An "effective amount," when used in conjunction with a compound, is an amount effective for treating or preventing a disease in a subject as described herein.
As used in this disclosure, the term "carrier" encompasses carriers, excipients, and diluents, and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting an agent from one organ or portion of the subject's body to another organ or portion of the subject's body.
As used herein, "treatment" describes the management and care of a patient for the purpose of reversing, inhibiting, or countering a disease, condition, or disorder, and includes administration of a compound of the present disclosure (i.e., a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof) to reverse the disease, condition, or disorder, eliminate the disease, condition, or disorder, or inhibit the course of the disease, condition, or disorder.
As used herein, "preventing" describes reducing or eliminating the onset of the symptoms or complications of a disease, condition, or disorder of the present disclosure (i.e., a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof).
Unless otherwise indicated, the term "disorder" is used in this disclosure to mean, and is used interchangeably with, the term disease, condition, or disease.
As used in this disclosure, the term "administering" refers to either administering the disclosed compound or a pharmaceutically acceptable salt or composition of the disclosed compound directly to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt or composition of the compound to a subject, which prodrug derivative or analog forms an equivalent amount of the active compound in the subject.
As used in this disclosure, the term "prodrug" means a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis) to the disclosed compound.
The present invention relates to compounds capable of inhibiting c-Kit or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, which are useful for treating diseases and disorders associated with the modulation of the c-Kit enzyme. The present invention also relates to compounds useful for inhibiting c-Kit or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.
In one embodiment, the compound of formula (I) has the structure of formula (Ia):
Figure GDA0003427688590000101
and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers thereof.
In another embodiment, the compound of formula (I) has the structure of formula (Ib):
Figure GDA0003427688590000102
and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers thereof.
In another embodiment, the compound of formula (I) has the structure of formula (Ic):
Figure GDA0003427688590000103
and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers thereof.
In another embodiment, the compound of formula (I) has the structure of formula (Id):
Figure GDA0003427688590000111
and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers thereof.
In another embodiment, the compound of formula (I) has the structure of formula (Ie):
Figure GDA0003427688590000112
and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers thereof.
In another embodiment, the compound of formula (I) has the structure of formula (If):
Figure GDA0003427688590000113
and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers thereof.
In another embodiment, the compound of formula (I) has the structure of formula (Ig):
Figure GDA0003427688590000121
and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers thereof.
In another embodiment, the compound of formula (I) has the structure of formula (Ih):
Figure GDA0003427688590000122
and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers thereof.
In some embodiments of the above formula, A is C 6-10 And (4) an aryl group. In another embodiment, a is 5 or 6 membered heteroaryl. In another embodiment, a is a 6 membered aryl. In another embodiment, a is 6 membered heteroaryl. In another embodiment, a is phenyl. In another embodiment, a is pyridinyl.
In some embodiments of the above formula, L is-C (O) NR 5 -. In another embodiment, L is-C (O) NH-.
In some embodiments of the above formula, L is-NR 5 C (O) -. In another embodiment, L is-NHC (O) -.
In some embodiments of the above formula, R 1 Is H, (C) 1 -C 3 ) Alkylamino or (C) 1 -C 3 ) A dialkylamino group. In another embodiment, R 1 Is H, (C) 1 -C 2 ) Alkylamino or (C) 1 -C 2 ) A dialkylamino group. In another embodiment, R 1 Is (C) 1 -C 2 ) Alkylamino or (C) 1 -C 2 ) A dialkylamino group. In another embodiment, R 1 Is H.
In some embodiments of the above formula, R 2 Is H, (C) 1 -C 4 ) Alkyl, - (C (R) 6a ) 2 ) p -(C 3 -C 7 ) Cycloalkyl, - (C (R) 6a ) 2 ) p -heterocycloalkyl, wherein said heterocycloalkyl comprises 4 to 7 membered rings and 1 to 3 heteroatoms selected from N, O and S, - (C (R) 6a ) 2 ) p -(C 6 -C 10 ) Aryl or- (C (R) 6a ) 2 ) p -heteroaryl, wherein said heteroaryl comprises a 5 or 6 membered ring and 1 to 3 heteroatoms selected from N, O and S, wherein said alkyl is interrupted by one to four R 7 Optionally substituted, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted with one to four R 9 Optionally substituted. At another placeIn one embodiment, R 2 Is (C) 1 -C 4 ) Alkyl, - (C (R) 6a ) 2 ) p -(C 3 -C 7 ) Cycloalkyl, - (C (R) 6a ) 2 ) p -heterocycloalkyl, wherein said heterocycloalkyl comprises 4 to 7 membered rings and 1 to 3 heteroatoms selected from N, O and S, - (C (R) 6a ) 2 ) p -(C 6 -C 10 ) Aryl or- (C (R) 6a ) 2 ) p -heteroaryl, wherein said heteroaryl comprises a 5 or 6 membered ring and 1 to 3 heteroatoms selected from N, O and S, wherein said aryl is interrupted by one or more R 7 Optionally substituted, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted with one or more R 9 Optionally substituted. In another embodiment, R 2 Is H or (C) 1 -C 4 ) Alkyl via one or more R 7 Optionally substituted. In another embodiment, R 2 Is H, - (C (R) 6a ) 2 ) p -(C 3 -C 7 ) Cycloalkyl, - (C (R) 6a ) 2 ) p -heterocycloalkyl, wherein said heterocycloalkyl comprises 4 to 7 membered rings and 1 to 3 heteroatoms selected from N, O and S, - (C (R) 6a ) 2 ) p -(C 6 -C 10 ) Aryl or- (C (R) 6a ) 2 ) p -heteroaryl, wherein said heteroaryl comprises a 5 or 6 membered ring and 1 to 3 heteroatoms selected from N, O and S, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl is interrupted by one or more R 9 Optionally substituted.
In another embodiment, R 2 Is H, (C) 1 -C 4 ) Alkyl, - (CH) 2 ) p -(C 3 -C 7 ) Cycloalkyl, - (CH) 2 ) p -heterocycloalkyl, wherein said heterocycloalkyl comprises 4 to 7 membered rings and 1 to 3 heteroatoms selected from N, O and S, - (CH) 2 ) p -(C 6 -C 10 ) Aryl or- (CH) 2 ) p -heteroaryl, wherein said heteroaryl comprises a 5 or 6 membered ring and 1 to 3 heteroatoms selected from N, O and S, wherein said aryl is interrupted by one or more R 7 Optionally substituted, wherein said cycloalkyl, heterocycloalkyl, arylOr heteroaryl via one or more R 9 Optionally substituted.
In another embodiment, R 2 Is H, (C) 1 -C 4 ) Alkyl, - (CH) 2 ) p -(C 3 -C 7 ) Cycloalkyl, - (CH) 2 ) p -heterocycloalkyl, wherein said heterocycloalkyl comprises 4 to 7 membered rings and 1 to 3 heteroatoms selected from N, O and S, - (CH) 2 ) p -(C 6 -C 10 ) Aryl or- (CH) 2 ) p -heteroaryl, wherein said heteroaryl comprises a 5 or 6 membered ring and 1 to 3 heteroatoms selected from N, O and S, wherein said alkyl is interrupted by one to four R 7 Optionally substituted, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted with one to four R 9 Optionally substituted.
In some embodiments of the above formula, each R 3 Independently at each occurrence is (C) 1 -C 3 ) Alkyl, (C) 1 -C 3 ) Alkoxy group, (C) 1 -C 3 ) Haloalkyl, (C) 1 -C 3 ) Haloalkoxy, halogen or OH. In another embodiment, each R is 3 Independently at each occurrence is (C) 1 -C 3 ) Alkyl, (C) 1 -C 3 ) Alkoxy group, (C) 1 -C 3 ) Haloalkyl or (C) 1 -C 3 ) A haloalkoxy group. In another embodiment, each R is 3 Independently at each occurrence is halogen or OH. In another embodiment, each R is 3 Independently at each occurrence is (C) 1 -C 3 ) Alkyl, (C) 1 -C 3 ) Alkoxy, halogen or OH. In another embodiment, each R is 3 Independently at each occurrence is (C) 1 -C 3 ) Haloalkyl, (C) 1 -C 3 ) Haloalkoxy, halogen or OH. In another embodiment, each R is 3 Independently at each occurrence is (C) 1 -C 3 ) Alkyl, (C) 1 -C 3 ) Alkoxy or halogen. In another embodiment, each R is 3 Independently at each occurrence is (C) 1 -C 3 ) Alkyl or halogen. In another embodimentIn each case, each R 3 Independently at each occurrence is (C) 1 -C 2 ) Alkyl or halogen.
In some embodiments of the above formula, each R 4 Independently at each occurrence is (C) 1 -C 3 ) Alkyl, (C) 1 -C 3 ) Alkoxy group, (C) 1 -C 3 ) Haloalkyl, (C) 1 -C 3 ) Haloalkoxy, halogen, -OH, CN, (C) 3 -C 7 ) Cycloalkyl, - (C (R) 6b ) 2 ) q -NH 2 、-(C(R 6b ) 2 ) q -(C 1 -C 6 ) Alkylamino, - (C (R) 6b ) 2 ) q -(C 1 -C 6 ) Dialkylamino, - (C (R) 6b ) 2 ) q -heterocycloalkyl, wherein said heterocycloalkyl comprises 4 to 7 membered rings and 1 to 3 heteroatoms selected from N, O and S, or- (C (R) 6b ) 2 ) q -heteroaryl, wherein said heteroaryl comprises a 5 or 6 membered ring and 1 to 3 heteroatoms selected from N, O and S, and wherein said heterocycloalkyl or said heteroaryl is optionally substituted with one or more substituents each independently selected from (C) 1 -C 6 ) Alkyl, -NH 2 、(C 1 -C 6 ) Alkylamino and (C) 1 -C 6 ) A dialkylamino group. In another embodiment, each R is 4 Independently at each occurrence is (C) 1 -C 3 ) Alkyl, (C) 1 -C 3 ) Alkoxy group, (C) 1 -C 3 ) Haloalkyl, (C) 1 -C 3 ) Haloalkoxy, halogen, -OH, CN, (C) 3 -C 7 ) Cycloalkyl, - (C (R) 6b ) 2 ) q -NH 2 、-(C(R 6b ) 2 ) q -(C 1 -C 6 ) Alkylamino, - (C (R) 6b ) 2 ) q -(C 1 -C 6 ) Dialkylamino, - (C (R) 6b ) 2 ) q -heterocycloalkyl, wherein said heterocycloalkyl comprises 4 to 7 membered rings and 1 to 3 heteroatoms selected from N, O and S, or- (C (R) 6b ) 2 ) q -heteroaryl, wherein the heteroaryl comprises a 5 or 6 membered ring and1 to 3 heteroatoms selected from N, O and S, and wherein said heterocycloalkyl or said heteroaryl is optionally substituted with one to four substituents each independently selected from (C) 1 -C 6 ) Alkyl, -NH 2 、(C 1 -C 6 ) Alkylamino and (C) 1 -C 6 ) A dialkylamino group.
In another embodiment, each R is 4 Independently at each occurrence is (C) 1 -C 3 ) Alkoxy group, (C) 1 -C 3 ) Haloalkoxy, halogen, CN, (C) 3 -C 7 ) Cycloalkyl, - (C (R) 6b ) 2 ) q -NH 2 、-(C(R 6b ) 2 ) q -(C 1 -C 6 ) Alkylamino, - (C (R) 6b ) 2 ) q -(C 1 -C 6 ) Dialkylamino, - (C (R) 6b ) 2 ) q -heterocycloalkyl, wherein said heterocycloalkyl comprises 4 to 7 membered rings and 1 to 3 heteroatoms selected from N, O and S, or- (C (R) 6b ) 2 ) q -heteroaryl, wherein said heteroaryl comprises a 5 or 6 membered ring and 1 to 3 heteroatoms selected from N, O and S, and wherein said heterocycloalkyl or said heteroaryl is optionally substituted with one to four substituents each independently selected from (C) 1 -C 6 ) Alkyl, -NH 2 、(C 1 -C 6 ) Alkylamino and (C) 1 -C 6 ) A dialkylamino group.
In another embodiment, each R is 4 Independently at each occurrence is (C) 1 -C 3 ) Alkoxy group, (C) 1 -C 3 ) Haloalkoxy, halogen, CN, (C) 3 -C 7 ) Cycloalkyl, - (C (R) 6b ) 2 ) q -NH 2 、-(C(R 6b ) 2 ) q -(C 1 -C 6 ) Alkylamino, - (C (R) 6b ) 2 ) q -(C 1 -C 6 ) Dialkylamino, - (C (R) 6b ) 2 ) q -heterocycloalkyl, wherein said heterocycloalkyl comprises 4 to 7 membered rings and 1 to 3 heteroatoms selected from N, O and S, or- (C (R) 6b ) 2 ) q -heteroaryl, wherein said heteroaryl comprises a 5 or 6 membered ring and 1 to 3 heteroatoms selected from N, O and S, and wherein said heterocycloalkyl or said heteroaryl is optionally substituted with one to four substituents each independently selected from (C) 1 -C 6 ) Alkyl, -NH 2 、(C 1 -C 6 ) Alkylamino and (C) 1 -C 6 ) A dialkylamino group.
In another embodiment, each R is 4 Independently at each occurrence is (C) 1 -C 3 ) Haloalkoxy, CN, (C) 3 -C 7 ) Cycloalkyl, - (C (R) 6b ) 2 ) q -NH 2 、-(C(R 6b ) 2 ) q -(C 1 -C 6 ) Alkylamino, - (C (R) 6b ) 2 ) q -(C 1 -C 6 ) Dialkylamino, - (C (R) 6b ) 2 ) q -heterocycloalkyl, wherein said heterocycloalkyl comprises 4 to 7 membered rings and 1 to 3 heteroatoms selected from N, O and S, or- (C (R) 6b ) 2 ) q -heteroaryl, wherein said heteroaryl comprises a 5 or 6 membered ring and 1 to 3 heteroatoms selected from N, O and S, and wherein said heterocycloalkyl or said heteroaryl is optionally substituted with one to four substituents each independently selected from (C) 1 -C 6 ) Alkyl, -NH 2 、(C 1 -C 6 ) Alkylamino and (C) 1 -C 6 ) A dialkylamino group. In another embodiment, each R is 4 Independently at each occurrence is (C) 1 -C 3 ) Haloalkoxy, CN, (C) 3 -C 7 ) Cycloalkyl, - (CH) 2 ) q -NH 2 、-(CH 2 ) q -(C 1 -C 6 ) Alkylamino, - (CH) 2 ) q -(C 1 -C 6 ) Dialkylamino, - (CH) 2 ) q -heterocycloalkyl, wherein said heterocycloalkyl comprises 4 to 7 membered rings and 1 to 3 heteroatoms selected from N, O and S, or- (CH) 2 ) q -heteroaryl, wherein said heteroaryl comprises a 5 or 6 membered ring and 1 to 3 heteroatoms selected from N, O and S, and wherein said heterocycloalkyl or said heteroaryl is substituted with one to four heteroatomsEach substituent is independently selected from (C) 1 -C 6 ) Alkyl, -NH 2 、(C 1 -C 6 ) Alkylamino and (C) 1 -C 6 ) A dialkylamino group.
In some embodiments of the above formula, R 5 Is H, (C) 1 -C 3 ) Alkyl or (C) 1 -C 3 ) A haloalkyl group. In another embodiment, R 5 Is (C) 1 -C 3 ) Alkyl or (C) 1 -C 3 ) A haloalkyl group. In another embodiment, R 5 Is H or (C) 1 -C 3 ) An alkyl group. In another embodiment, R 5 Is H, methyl, ethyl, n-propyl or isopropyl. In another embodiment, R 5 Is H, methyl or ethyl. In another embodiment, R 5 Is methyl or ethyl. In another embodiment, R 5 Is H.
In some embodiments of the above formula, R 6a Is H or (C) 1 -C 3 ) An alkyl group. In another embodiment, R 6a Is H or (C) 1 -C 2 ) An alkyl group. In another embodiment, R 6a Is (C) 1 -C 3 ) An alkyl group. In another embodiment, R 6a Is H.
In some embodiments of the above formula, R 6b Is H or (C) 1 -C 3 ) An alkyl group. In another embodiment, R 6b Is H or (C) 1 -C 2 ) An alkyl group. In another embodiment, R 6b Is (C) 1 -C 3 ) An alkyl group. In another embodiment, R 6b Is H.
In some embodiments of the above formula, R 7 Is (C) 1 -C 3 ) Alkoxy group, (C) 1 -C 3 ) Haloalkoxy, -OH, -NH 2 、(C 1 -C 3 ) Alkylamino radical, (C) 1 -C 3 ) Dialkylamino or-C (O) N (R) 8 ) 2 . In another embodiment, R 7 Is (C) 1 -C 3 ) Alkoxy, -OH, -NH 2 、(C 1 -C 3 ) Alkylamino radical, (C) 1 -C 3 ) Dialkylamino or-C (O) N (R) 8 ) 2 . In another embodiment, R 7 Is (C) 1 -C 3 ) Alkoxy group, (C) 1 -C 3 ) Alkylamino radical, (C) 1 -C 3 ) Dialkylamino or-C (O) N (R) 8 ) 2 . In another embodiment, R 7 Is (C) 1 -C 3 ) Alkoxy group, (C) 1 -C 3 ) Dialkylamino or-C (O) N (R) 8 ) 2 。
In some embodiments of the above formula, R 8 Independently H, (C) 1 -C 3 ) Alkyl or (C) 1 -C 3 ) A haloalkyl group. In another embodiment, R 8 Is (C) 1 -C 3 ) Alkyl or (C) 1 -C 3 ) A haloalkyl group. In another embodiment, R 8 Is H or (C) 1 -C 3 ) An alkyl group. In another embodiment, R 8 Is H, methyl, ethyl, n-propyl or isopropyl. In another embodiment, R 8 Is methyl or ethyl. In another embodiment, R 8 Is H. In another embodiment, R 8 Is H, methyl or ethyl.
In some embodiments of the above formula, each R 9 Independently at each occurrence is (C) 1 -C 3 ) Alkyl, (C) 1 -C 3 ) Haloalkyl, -C (O) H, -C (O) (C) 1 -C 3 ) An alkyl or 5 to 7 membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from N, O and S, wherein said heterocycloalkyl is optionally substituted with one to four substituents each independently selected from (C) 1 -C 6 ) Alkyl, -C (O) H or-C (O) (C) 1 -C 6 ) An alkyl group, and wherein the alkyl group is optionally substituted with one to four substituents each independently selected from (C) 1 -C 6 ) Alkoxy, -OH, (C) 1 -C 6 ) Haloalkoxy, -NH 2 、(C 1 -C 6 ) Alkylamino or (C) 1 -C 6 ) A dialkylamino group.
In another embodiment, eachR is 9 Independently at each occurrence is (C) 1 -C 3 ) Alkyl, -C (O) (C) 1 -C 3 ) An alkyl or 5 to 7 membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from N, O and S, wherein said heterocycloalkyl is optionally substituted with one to four substituents each independently selected from (C) 1 -C 6 ) Alkyl, -C (O) H or-C (O) (C) 1 -C 6 ) An alkyl group, and wherein the alkyl group is optionally substituted with one to four substituents each independently selected from (C) 1 -C 6 ) Alkoxy, -OH, (C) 1 -C 6 ) Haloalkoxy, -NH 2 、(C 1 -C 6 ) Alkylamino or (C) 1 -C 6 ) A dialkylamino group. In another embodiment, each R is 9 Independently at each occurrence is (C) 1 -C 3 ) An alkyl or 5 to 7 membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from N, O and S, wherein said heterocycloalkyl is optionally substituted with one to four substituents each independently selected from (C) 1 -C 6 ) Alkyl, -C (O) H or-C (O) (C) 1 -C 6 ) An alkyl group, and wherein the alkyl group is optionally substituted with one to four substituents each independently selected from (C) 1 -C 6 ) Alkoxy, -OH, (C) 1 -C 6 ) Haloalkoxy, -NH 2 、(C 1 -C 6 ) Alkylamino or (C) 1 -C 6 ) A dialkylamino group.
In another embodiment, each R is 9 Independently at each occurrence is (C) 1 -C 3 ) An alkyl or 5 to 7 membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from N, O and S, wherein said heterocycloalkyl is optionally substituted with one to four substituents each independently selected from (C) 1 -C 6 ) Alkyl, -C (O) H or-C (O) (C) 1 -C 6 ) An alkyl group, and wherein the alkyl group is optionally substituted with one to four substituents each independently selected from (C) 1 -C 6 ) Alkoxy, -OH or (C) 1 -C 6 ) A dialkylamino group.
In some embodiments of the above formula, n is 0, 1 or 2. In another embodiment, n is 0 or 1. In another embodiment, n is 1 or 2. In another embodiment, n is 0. In another embodiment, n is 1. In another embodiment, n is 2.
In some embodiments of the above formula, p is 0, 1 or 2. In another embodiment, p is 0 or 1. In another embodiment, p is 1 or 2. In another embodiment, p is 0. In another embodiment, p is 1. In another embodiment, p is 2.
In some embodiments of the above formula, q is 0, 1, or 2. In another embodiment, q is 0 or 1. In another embodiment, q is 1 or 2. In another embodiment, q is 0. In another embodiment, q is 1. In another embodiment, q is 2.
In some embodiments of the above formula, L is-C (O) NR 5 -。
In some embodiments of the above formula, L is-NR 5 C(O)-。
In some embodiments of the above formula, R 3 Is (C) 1 -C 6 ) Alkyl or halogen.
In some embodiments of the above formula, R 3 Is methyl or F.
In some embodiments of the above formula, R 3 Is methyl.
In some embodiments of the above formula, R 1 Is H.
In some embodiments of the above formula, A is via one or two R 4 Optionally substituted (C) 6 -C 10 ) And (4) an aryl group.
In some embodiments of the above formula, A is via one or two R 4 Optionally substituted 6-membered heteroaryl;
in some embodiments of the above formula, A is via one or two R 4 Optionally substituted phenyl or pyridyl.
In some embodiments of the above formula, A is via one R 4 Substituted phenyl or pyridyl.
Some embodiments of the above formulaIn the scheme, A is two groups of R 4 Substituted phenyl or pyridyl.
In some embodiments of the above formula, R 5 Is H.
In some embodiments of the above formula, n is 0.
In some embodiments of the above formula, n is 1.
In some embodiments of the above formula, A is via one R 4 Substituted phenyl or pyridyl and R 4 Is CF 3 Or a cyclopropyl group.
In some embodiments of the above formula, A is two R 4 Substituted phenyl or pyridyl and at least one R 4 Is CF 3 。
In some embodiments of the above formula, n is 1 and R is 3 Is methyl.
In some embodiments of the above formula, R 1 Is H.
In some embodiments of the above formula, one R 4 Is (C) 1 -C 6 ) Haloalkyl and another R 4 Is CN, - (CH) 2 )-(C 1 -C 6 ) Dialkylamino, -heterocycloalkyl or- (CH) 2 ) -heterocycloalkyl, wherein said heterocycloalkyl comprises 4 to 7 membered rings and 1 to 3 heteroatoms selected from N, O and S, wherein said heterocycloalkyl is interrupted by one or more (C) 1 -C 3 ) The alkyl group is optionally substituted.
In some embodiments of the above formula, one R is 4 Is CF 3 And the other R 4 Is CN, - (CH) 2 )-(C 1 -C 6 ) Dialkylamino, -heterocycloalkyl or- (CH) 2 ) -heterocycloalkyl, wherein said heterocycloalkyl comprises 4 to 7 membered rings and 1 to 3 heteroatoms selected from N, O and S, wherein said heterocycloalkyl is interrupted by one or more (C) 1 -C 3 ) The alkyl group is optionally substituted.
In some embodiments of the above formula, one R is 4 Is CF 3 And the other R 4 Is CN, - (CH) 2 )-N(CH 3 ) 2 Piperazinyl, - (CH) 2 ) -piperazinyl, - (CH) 2 ) -morpholinyl or- (CH) 2 ) -azolesAlkyl, wherein said piperazine, morpholino or pyrrolidinyl is substituted with one or more (C) 1 -C 3 ) The alkyl group is optionally substituted.
In some embodiments of the above formula, one R is 2 Is (C) 1 -C 6 ) Alkyl or- (C (R) 6b ) 2 ) q -heteroaryl, wherein the heteroaryl comprises a 5 or 6 membered ring and 1 to 3 heteroatoms selected from N, O and S, and via one to two (C) 1 -C 6 ) Alkyl substitution.
In some embodiments of the above formula, one R is 2 Is CH 3 Or heteroaryl, wherein the heteroaryl comprises a 5 or 6 membered ring and 1 to 3 heteroatoms selected from N, O and S, and is mono-to di- (C) 1 -C 6 ) Alkyl substitution.
In some embodiments of the above formula, one R is 2 Is CH 3 Or through one to two (C) 1 -C 6 ) Alkyl-substituted pyrazolyl.
In some embodiments of the above formula, R 4 Is (C) 1 -C 6 ) A haloalkyl group.
In some embodiments of the above formula, R 4 Is CF 3 。
In some embodiments of the above formula, n is 1,R 3 Is methyl, R 1 Is H, and R 2 Is H; CH (CH) 3 ；CH 2 CH 3 ；-(CH 2 ) 2 N(CH 3 ) 2 ；-(CH 2 ) 3 N(CH 3 ) 2 ；-CH 2 C(O)NH(CH 3 )；-(CH 2 ) 2 Morpholinyl;
-(CH 2 ) 2 OCH 3 (ii) a Piperidinyl substituted with methyl; phenyl optionally substituted with 4-methylpiperazine; -CH 2 -a pyridyl group; a cyclopropyl group; a methyl-substituted triazolyl group; or imidazolyl substituted with methyl or N-methylpiperidinyl.
In some embodiments of the above formula, n is 1 and R is 3 Is methyl, R 1 Is pyrazolyl optionally substituted with methyl; - (CH) 2 ) 2 OH；-(CH 2 ) 2 OCH 3 ；-(CH 2 ) 2 N(CH 3 ) 2 ；
-(CH 2 ) 2 N(CH 2 CH 3 ) 2 (ii) a Morpholinyl; or piperidinyl optionally substituted with methyl or-C (O) H.
In some embodiments of the above formula, n is 0 or 1 and R is 3 Is F, R 1 Is pyrazolyl optionally substituted by methyl.
In some embodiments of the above formula, n is 1,R 3 Is methyl, R 1 Is NH 2 And R is 2 Is H.
In some embodiments of the above formula, L is-C (O) NR 5 And A is via one to four R 4 Optionally substituted (C) 6 -C 10 ) And (4) an aryl group. In another embodiment, L is-C (O) NR 5 -, A is via one to four R 4 Optionally substituted (C) 6 -C 10 ) Aryl, and R 1 Is H. In another embodiment, L is-C (O) NR 5 -, A is via one to four R 4 Optionally substituted (C) 6 -C 10 ) Aryl, R 1 Is H, and R 3 Is (C) 1 -C 6 ) Alkyl or halogen. In another embodiment, L is-C (O) NR 5 -, A is via one to four R 4 Optionally substituted (C) 6 -C 10 ) Aryl radical, R 1 Is H, R 3 Is (C) 1 -C 6 ) Alkyl or halogen, and n is 1. In another embodiment, L is-C (O) NR 5 A is through one to four R 4 Optionally substituted (C) 6 -C 10 ) Aryl radical, R 1 Is H, R 3 Is (C) 1 -C 6 ) Alkyl or halogen, n is 1, and R 5 Is H. In another embodiment, L is-C (O) NR 5 -, A is via one to four R 4 Optionally substituted (C) 6 -C 10 ) Aryl radical, R 1 Is H, and n is 0. In another embodiment, L is-C (O) NR 5 -, A is via one to four R 4 Optionally substituted (C) 6 -C 10 ) Aryl radical, R 1 Is H, n is 0, and R 5 Is H.
In some embodiments of the above formula, L is-C (O) NR 5 And A is via one to four R 4 Optionally substituted 5-to 10-membered heteroaryl. In another embodiment, L is-C (O) NR 5 -, A is via one to four R 4 Optionally substituted 5-to 10-membered heteroaryl, and R 1 Is H. In another embodiment, L is-C (O) NR 5 -, A is via one to four R 4 Optionally substituted 5-to 10-membered heteroaryl, R 1 Is H, and R 3 Is (C) 1 -C 6 ) Alkyl or halogen. In another embodiment, L is-C (O) NR 5 A is through one to four R 4 Optionally substituted 5-to 10-membered heteroaryl, R 1 Is H, R 3 Is (C) 1 -C 6 ) Alkyl or halogen, and n is 1. In another embodiment, L is-C (O) NR 5 -, A is via one to four radicals R 4 Optionally substituted 5-to 10-membered heteroaryl, R 1 Is H, R 3 Is (C) 1 -C 6 ) Alkyl or halogen, n is 1, and R 5 Is H. In another embodiment, L is-C (O) NR 5 -, A is via one to four R 4 Optionally substituted 5-to 10-membered heteroaryl, R 1 Is H, and n is 0. In another embodiment, L is-C (O) NR 5 -, A is via one to four R 4 Optionally substituted 5-to 10-membered heteroaryl, R 1 Is H, n is 0, and R 5 Is H.
In some embodiments of the above formula, L is-NR 5 C (O) -and A is through one to four R 4 Optionally substituted (C) 6 -C 10 ) And (4) an aryl group. In another embodiment, L is-NR 5 C (O) -, A is through one to four R 4 Optionally substituted (C) 6 -C 10 ) Aryl, and R 1 Is H. In another embodiment, L is-NR 5 C (O) -, A is through one to four R 4 Optionally substituted (C) 6 -C 10 ) Aryl, R 1 Is H, and R 3 Is (C) 1 -C 6 ) Alkyl or halogen. In another embodiment, L is-NR 5 C (O) -, A is through one to four R 4 Optionally substituted(C 6 -C 10 ) Aryl radical, R 1 Is H. R 3 Is (C) 1 -C 6 ) Alkyl or halogen, and n is 1. In another embodiment, L is-NR 5 C (O) -, A is through one to four R 4 Optionally substituted (C) 6 -C 10 ) Aryl radical, R 1 Is H. R 3 Is (C) 1 -C 6 ) Alkyl or halogen, n is 1, and R 5 Is H. In another embodiment, L is-NR 5 C (O) -, A is through one to four R 4 Optionally substituted (C) 6 -C 10 ) Aryl radical, R 1 Is H, and n is 0. In another embodiment, L is-NR 5 C (O) -, A is through one to four R 4 Optionally substituted (C) 6 -C 10 ) Aryl radical, R 1 Is H, n is 0, and R 5 Is H.
In some embodiments of the above formula, L is-NR 5 C (O) -and A is through one to four R 4 Optionally substituted 5-to 10-membered heteroaryl. In another embodiment, L is-NR 5 C (O) -, A is through one to four aryl radicals R 4 Optionally substituted 5-to 10-membered hetero, and R 1 Is H. In another embodiment, L is-NR 5 C (O) -, A is through one to four R 4 Optionally substituted 5-to 10-membered heteroaryl, R 1 Is H, and R 3 Is (C) 1 -C 6 ) Alkyl or halogen. In another embodiment, L is-NR 5 C (O) -, A is through one to four R 4 Optionally substituted 5-to 10-membered heteroaryl, R 1 Is H, R 3 Is (C) 1 -C 6 ) Alkyl or halogen, and n is 1. In another embodiment, L is-NR 5 C (O) -, A is through one to four R 4 Optionally substituted 5-to 10-membered heteroaryl, R 1 Is H, R 3 Is (C) 1 -C 6 ) Alkyl or halogen, n is 1, and R 5 Is H. In another embodiment, L is-NR 5 C (O) -, A is through one to four R 4 Optionally substituted 5-to 10-membered heteroaryl, R 1 Is H, and n is 0. In another embodiment, L is-NR 5 C (O) -, A is through one to four R 4 Optionally substituted5 to 10 membered heteroaryl of (A), R 1 Is H, n is 0, and R 5 Is H.
Non-limiting illustrative compounds of the invention include:
4-methyl-3- ((1- (2- (methylamino) -2-oxoethyl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-1);
3- ((1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-2);
3- ((1- (2- (dimethylamino) ethyl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-3);
3- ((1- (2-methoxyethyl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-4);
4-methyl-3- ((1- (2-morpholinoethyl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-5);
3- ((1- (3- (dimethylamino) propyl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-6);
3- ((1-ethyl-1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-7);
4-methyl-3- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-8);
3- ((2-amino-1H-benzo [ d ] imidazol-6-yl) ethynyl) -4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-10);
4-methyl-3- ((1-methyl-1H-benzo [ d ] imidazol-6-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-11);
4-methyl-3- ((1- (pyridin-3-ylmethyl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-12);
3- ((1-cyclopropyl-1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-13);
4-methyl-3- ((1- (3- (4-methylpiperazin-1-yl) phenyl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-14);
4-methyl-3- ((1- (4- (4-methylpiperazin-1-yl) phenyl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-15);
4-methyl-3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-17);
n- (4-methyl-3- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) ethynyl) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) benzamide (I-18);
4-methyl-3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-19);
4-methyl-3- ((1- (1-methylpiperidin-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-20);
4-methyl-3- ((1-phenyl-1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-21);
4-methyl-3- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) benzamide (I-22);
4-methyl-3- ((1- (1-methyl-1H-imidazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-23);
4-methyl-3- ((1- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-24);
3- ((1- (1- (1-formylpiperidin-4-yl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-25);
4-methyl-3- ((1- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-26);
4-methyl-3- ((1- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-27);
n- (3-cyclopropylphenyl) -4-methyl-3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) benzamide (I-28);
4-methyl-3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (pyrrolidin-1-ylmethyl) -3- (trifluoromethyl) phenyl) benzamide (I-29);
4-methyl-3- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (pyrrolidin-1-ylmethyl) -3- (trifluoromethyl) phenyl) benzamide (I-30);
3- ((1- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-31);
3- ((1- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-32);
4-methyl-3- ((1- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-33);
4-methyl-3- ((1- (1- (1-methylpiperidin-4-yl) -1H-imidazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-34);
3- ((1- (1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-35);
n- (4-methyl-3- ((1- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) phenyl) -4- (trifluoromethyl) picolinamide (I-36);
n- (4-cyano-3- (trifluoromethyl) phenyl) -4-methyl-3- ((1- (1-methyl-1H-pyrazol-3-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) benzamide (I-37);
n- (3- ((1- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methylphenyl) -4- (trifluoromethyl) picolinamide (I-38);
n- (3- ((1- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methylphenyl) -4- (trifluoromethyl) picolinamide (I-39);
n- (3- ((1- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methylphenyl) -4- (trifluoromethyl) picolinamide (I-40);
n- (3- ((1- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methylphenyl) -4- (trifluoromethyl) picolinamide (I-41);
n- (3- ((1- (1- (2- (diethylamino) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methylphenyl) -4- (trifluoromethyl) picolinamide (I-42);
n- (3- ((1- (1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methylphenyl) -4- (trifluoromethyl) picolinamide (I-43);
n- (4-methyl-3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) phenyl) -4- (trifluoromethyl) picolinamide (I-44);
n- (4-methyl-3- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) ethynyl) phenyl) -4- (trifluoromethyl) picolinamide (I-45);
n- (4-methyl-3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) benzamide (I-46);
n- (4-methyl-3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) phenyl) -4- (pyrrolidin-1-ylmethyl) -3- (trifluoromethyl) benzamide (I-47);
n- (4-methyl-3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) phenyl) -4- (morpholinomethyl) -3- (trifluoromethyl) benzamide (I-48);
n- (3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) phenyl) -4- (trifluoromethyl) picolinamide (I-49);
3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-50);
4-fluoro-3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide); (I-51); and
n- (4-fluoro-3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) phenyl) -4- (trifluoromethyl) picolinamide (I-52).
In another embodiment of the invention, the compound of formula (I) is an enantiomer: in some embodiments, the compound is the (S) -enantiomer. In some embodiments, the compound is the (R) -enantiomer. In other embodiments, the compound of formula (I) may be the (+) or (-) enantiomer.
It is to be understood that all isomeric forms are included in the present invention, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have either the cis or trans configuration. All tautomeric forms are also intended to be included.
The compounds of the present invention and pharmaceutically acceptable salts, hydrates, solvates, stereoisomers and prodrugs thereof may exist in their tautomeric form (e.g., as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention and mixtures thereof, including racemic mixtures, form part of the invention. In addition, the present invention includes all geometric and positional isomers. For example, if the compounds of the present invention incorporate double bonds or fused rings, both the cis and trans forms, as well as mixtures, are included within the scope of the present invention. Each compound disclosed herein includes all enantiomers that conform to the general structure of the compound. The compounds may be in racemic or enantiomerically pure form, or in any other form with respect to stereochemistry. The assay results may reflect data collected in racemic form, enantiomerically pure form, or any other form in terms of stereochemistry.
Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physicochemical differences by methods well known to those skilled in the art, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by: the enantiomeric mixture is converted into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), the diastereomers are separated and the individual diastereomers are converted (e.g., hydrolyzed) to the corresponding pure enantiomers. Moreover, some of the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered to be part of the present invention. Enantiomers can also be separated using a chiral HPLC column.
The compounds of the invention may also exist in different tautomeric forms and all such forms are included within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
All stereoisomers (e.g., geometric isomers, optical isomers, etc.) (including those of salts, solvates, esters, and prodrugs of the compounds, and salts, solvates, and esters of prodrugs) of the compounds of the present invention, such as those that may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are also contemplated within the scope of the invention, as are positional isomers (e.g., 4-pyridyl and 3-pyridyl). (for example, if the compound of formula (I) incorporates a double bond or fused ring, both the cis and trans forms, as well as mixtures, are included within the scope of the invention likewise, for example, all keto-enol and imine-enamine forms of the compound are also included in the invention.) the individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be mixed, for example, as a racemate or with all other stereoisomers or other selected stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined in the IUPAC Recommendation (IUPAC 1974 Recommendation) of 1974. The use of the terms "salt", "solvate", "ester", "prodrug" and the like is intended to apply equally to the salts, solvates, esters and prodrugs of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the compounds of the present invention.
The compounds of formula (I) may form salts, and such salts are also within the scope of the present invention. Unless otherwise indicated, reference to the compounds of the formulae herein is understood to include reference to salts thereof.
The present invention relates to compounds that are modulators of c-Kit. In one embodiment, the compounds of the invention are inhibitors of c-Kit.
The present invention relates to compounds as described herein and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, as well as pharmaceutical compositions comprising one or more compounds as described herein or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof.
Methods for synthesizing said compounds
The compounds of the present invention can be prepared by a variety of methods, including standard chemical methods. Suitable synthetic routes are described in the schemes given below.
The compounds of formula (I) may be prepared by methods known in the art of organic synthesis, as illustrated in part by the synthetic schemes below. In the schemes described below, it is well understood that protective groups for sensitive or reactive groups may be employed as necessary, according to general principles or chemistry. The protecting Groups were manipulated according to standard methods of Organic Synthesis (T.W.Greene and P.G.M.Wuts, "Protective Groups in Organic Synthesis", 3 rd edition, wiley, new York 1999). These groups are removed at a convenient stage of compound synthesis using methods apparent to those skilled in the art. The selection procedure as well as the reaction conditions and their order of execution are in accordance with the preparation of the compounds of the formula (I).
One skilled in the art will recognize whether stereocenters are present in the compounds of formula (I). Thus, the present invention includes both possible stereoisomers (unless otherwise indicated in the synthesis) and includes not only racemic compounds, but also individual enantiomers and/or diastereomers. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. The resolution of the final product, intermediate or starting material may be effected by any suitable method known in the art. See, e.g., "Stereochemistry of Organic Compounds" by E.L.Eliel, S.H.Wilen, and L.N.Mander (Wiley-lnterscience, 1994).
The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic methods.
Preparation of the Compounds
The compounds of the present invention can be prepared by a number of methods well known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the art of synthetic organic chemistry, or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The starting materials are either commercially available or prepared by known methods in the reported literature. The compounds of the invention can be synthesized according to the procedures outlined in general schemes 1 and 2, including the assembly of intermediates 2a-2j and 3a-2 c. The starting materials are either commercially available or prepared by known methods in the reported literature.
General scheme 1
Figure GDA0003427688590000241
Of which A, R 1 -R 3 、R 5 And n is as defined for formula (I).
The preparation of compounds wherein L is-C (O) NR by using intermediates 2a-2j is outlined above in general scheme 1 5 General manner of the target compounds of formula (I) of (I). In the presence of a base (i.e., potassium carbonate (K) 2 CO 3 ) Or sodium carbonate (Na) 2 CO 3 ) And a solvent (i.e.Nucleophilic addition of amines 2b to 2a at elevated temperature in the presence of Acetonitrile (ACN)) gives intermediates 2c. Optionally at elevated temperature, in the presence of a metal (i.e., zinc), ammonium chloride (NH) 4 Cl) and a solvent (i.e., acetone/water) to afford intermediate 2d. Intermediate 2d is cyclized with 2e2 optionally in a solvent (i.e., isopropanol), optionally at elevated temperature, to afford intermediate 2f. Alternatively, intermediate 2f may be prepared in one step using a metal (i.e., iron), ammonium chloride (NH) 4 Cl) and a solvent (i.e., isopropanol) are obtained from intermediates 2c and 2e1 at elevated temperature. Intermediate 2i was obtained as follows: intermediate 2g is treated with thionyl chloride, optionally in the presence of a solvent, to form the acid chloride, followed by the use of a base (i.e., N-diisopropylethylamine (i-Pr) 2 NEt)) and 4-Dimethylaminopyridine (DMAP) and optionally in a solvent (i.e. dichloromethane (CH)) 2 Cl 2 ) In 2 h) the amine is acylated with the acid chloride formed. In tetrakis (triphenylphosphine) palladium (0) (Pd (PPh) 3 ) 4 ) Copper iodide, alkali (i.e., i-Pr) 2 NEt) with alkyne 2j optionally coupled with bromide 2f optionally at elevated temperature, optionally in the presence of a solvent (i.e. ACN), to provide the desired compound of formula (I) wherein L is-C (O) NR 5 -。
General scheme 2
Figure GDA0003427688590000251
Of which A, R 1 -R 3 、R 5 And n is as defined for formula (I).
The preparation of compounds wherein L is-NR by using intermediates 2e and 3a-3d is outlined above in general scheme 2 5 General manner of the target compounds of formula (I) of C (O) -. Intermediate 3c was obtained as follows: intermediate 3b is treated with thionyl chloride, optionally in the presence of a solvent, to form the acid chloride, followed by the use of a base (i.e., N-diisopropylethylamine (i-Pr) 2 NEt)) and 4-Dimethylaminopyridine (DMAP) and optionally in a solvent (i.e. dichloromethane (CH)) 2 Cl 2 ) In (c), the amine 3b is acylated with the acid chloride formed. In tetrakis (triphenylphosphine) palladium (0) (Pd (PPh) 3 ) 4 ) Iodine, iodineDissolving copper and alkali (i.e. i-Pr) 2 NEt) with a bromide 2f, optionally at elevated temperature, optionally in the presence of a solvent (i.e. ACN), to provide the desired compound of formula (I), wherein L is-NR 5 C(O)-。
The compounds of formula (I) may exist as enantiomeric or diastereomeric stereoisomers. Enantiomerically pure compounds of formula (I) can be prepared using a chiral building block (chiral building block). Alternatively, a racemic mixture of the final compound or a racemic mixture of a higher intermediate may be subjected to chiral purification, as described below, to deliver the desired enantiomerically pure intermediate or final compound. In the case of purification of the higher intermediate into its individual enantiomers, each individual enantiomer may be carried separately to deliver the final enantiomerically pure compound of formula (I).
It is to be understood that in the descriptions and formulas shown above, the various groups R unless otherwise indicated 1 -R 5 、R 6a 、R 6b 、R 7 -R 9 L, a, n, p and q, and other variables are as defined above. Furthermore, for synthetic purposes, the compounds of general schemes 1 and 2 are merely representative of those having selected groups to illustrate the general synthetic methods of compounds of formula (I) as defined herein.
Methods of using the disclosed compounds
Another aspect of the invention relates to methods of treating diseases or disorders associated with the modulation of c-Kit. The method comprises administering to a patient in need of treatment of a disease or condition associated with modulation of c-Kit an effective amount of a composition and a compound of formula (I).
Another aspect of the invention relates to methods of preventing diseases or disorders associated with the modulation of c-Kit. The method comprises administering to a patient in need of treatment of a disease or disorder associated with the modulation of c-Kit an effective amount of a composition and a compound of formula (I).
Another aspect of the invention relates to methods of treating a c-Kit mediated disease or condition. The method comprises administering to a patient in need of treatment of a disease or disorder associated with the modulation of c-Kit an effective amount of a composition and a compound of formula (I).
Another aspect of the invention relates to a method of preventing a c-Kit mediated disease or condition. The method comprises administering to a patient in need of treatment of a disease or disorder associated with the modulation of c-Kit an effective amount of a composition and a compound of formula (I).
In another aspect, the invention relates to a method of inhibiting c-Kit. The method involves administering to a patient in need thereof an effective amount of a compound of formula (I).
Another aspect of the invention relates to a method of treating a disease or disorder associated with the inhibition of c-Kit in a patient, comprising administering to a patient in need thereof an effective amount of a compound of formula (I). In one embodiment, the disease or disorder is selected from cancer and cell proliferative disorders, multiple sclerosis, asthma, mastocytosis, inflammatory disorders, allergic reactions, fibrotic disorders, and metabolic disorders.
Another aspect of the invention relates to a method of preventing a disease or disorder associated with the inhibition of c-Kit in a patient, comprising administering to a patient in need thereof an effective amount of a compound of formula (I).
The invention also relates to the use of a c-Kit inhibitor for the manufacture of a medicament for the treatment, prevention, inhibition or elimination of a disease or condition mediated by c-Kit, wherein the medicament comprises a compound of formula (I).
In another aspect, the invention relates to a method for the manufacture of a medicament for the treatment, prevention, inhibition or elimination of a disease or condition mediated by c-Kit, wherein the medicament comprises a compound of formula (I).
Another aspect of the invention relates to compounds of formula (I) for use in the manufacture of a medicament for the treatment of a disease or condition associated with the inhibition of c-Kit.
In another aspect, the invention relates to the use of a compound of formula (I) for the treatment of a disease or disorder associated with the inhibition of c-Kit.
In another aspect, the invention relates to the use of a compound of formula (I) for the prevention of a disease or disorder associated with the inhibition of c-Kit.
In some embodiments of the above method, the disease or disorder is selected from the group consisting of cancer, metastatic disease, inflammation and autoimmune pathogenesis.
In some embodiments of the above methods, the disease or disorder is selected from a cell proliferative disorder, a fibrotic disorder, and a metabolic disorder.
In one embodiment of the above method, the disease or disorder is multiple sclerosis.
In one embodiment of the above method, the disease or disorder is asthma. In another embodiment of the above method, the disease or condition is mastocytosis.
In one embodiment of the above method, the disease or condition is an allergic reaction.
In one embodiment of the above method, the disease or disorder is inflammatory arthritis.
Another aspect of the invention relates to a method of treating cancer. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I).
In some embodiments, the cancer is selected from liposarcoma, neuroblastoma, glioblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, oropharyngeal cancer, penile cancer, anal cancer, thyroid cancer, vaginal cancer, gastric cancer, rectal cancer, thyroid cancer, hodgkin lymphoma (Hodgkin lymphoma), and diffuse large B-cell lymphoma.
In some embodiments, the cancer is selected from leukemia, mast cell tumor, small cell lung cancer, testicular cancer, gastrointestinal cancer, central nervous system cancer, female genital tract cancer, sarcoma of neuroectodermal origin, and schwannoma associated with neurofibromatosis.
In some embodiments, the cancer is selected from small cell lung cancer, acute Myeloid Leukemia (AML), thymus cancer, desmoid tumor, neuroblastoma, malignant melanoma, colorectal cancer, systemic Mastocytosis (SM), and gastrointestinal stromal tumor (GIST).
Another aspect of the invention relates to methods of inducing cell cycle arrest, tumor cell apoptosis and/or enhanced tumor-specific T cell immunity. The method comprises contacting the cell with an effective amount of a compound of formula (I).
In one embodiment, the invention relates to the use of a c-Kit inhibitor for the manufacture of a medicament for the treatment, prevention, inhibition, or elimination of diseases or disorders associated with cancer and metastatic disease.
In some embodiments, administration of a compound of formula (I) or a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier induces a change in cell cycle or cell viability.
Another aspect of the invention relates to a method of treating inflammation. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I).
Another aspect of the invention relates to methods of treating autoimmune pathogenesis. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I).
Another aspect of the invention relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may also include excipients, diluents or surfactants.
In one embodiment, methods of treating diseases or disorders associated with the modulation of c-Kit, including cancer and cell proliferative disorders, multiple sclerosis, asthma, inflammatory disorders, allergic reactions, fibrotic disorders and metabolic disorders, are provided, comprising administering a compound of formula (I) to a patient suffering from at least one of said diseases or disorders.
In one embodiment, a method is provided for treating diseases or disorders associated with the modulation of c-Kit, including cancer and metastatic disease, comprising administering a compound of formula (I) to a patient suffering from at least one such disease or disorder.
One therapeutic use of a compound or composition of the invention that inhibits c-Kit is to provide treatment to a patient or subject suffering from cancer and cell proliferative disorders, multiple sclerosis, asthma, inflammatory disorders, allergic reactions, fibrotic disorders and metabolic disorders.
Another therapeutic use of a compound or composition of the invention that inhibits c-Kit is to provide treatment to a patient or subject suffering from cancer and metastatic disease.
The compounds disclosed herein can be administered in an effective amount to treat or prevent a disorder and/or prevent the development of a disorder in a subject.
Administration of the disclosed compounds can be accomplished by any mode of administration of the therapeutic agent. These modes include systemic or topical administration, for example oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical modes of administration.
Depending on the intended mode of administration, the disclosed compositions may be in solid, semi-solid, or liquid dosage forms, such as injections, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, and the like, sometimes in unit doses and consistent with conventional pharmaceutical practice. Likewise, the disclosed compositions can also be administered in intravenous (bolus and infusion), intraperitoneal, subcutaneous, or intramuscular forms, and all using forms well known to those skilled in the art of pharmacy.
Exemplary pharmaceutical compositions are tablets and gelatin capsules comprising a compound of the invention and a pharmaceutically acceptable carrier, such as a) a diluent, for example, purified water, triglyceride oil (such as hydrogenated or partially hydrogenated vegetable oil or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil (such as EPA or DHA), or esters or triglycerides thereof or mixtures thereof), omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) Lubricants, for example silica, talc, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol; for tablets, further comprising; c) Binders, for example magnesium aluminium silicate, starch paste, gelatin, gum tragacanth, methyl cellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums (such as gum acacia, gum tragacanth or sodium alginate), waxes and/or polyvinylpyrrolidone (if desired); d) Disintegrating agents, such as starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) Absorbents, colorants, flavorants and sweeteners; f) Emulsifying or dispersing agents, such as Tween 80, labrasol, HPMC, DOSS, hexanoyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS, or other acceptable emulsifying agents; and/or g) agents that enhance the absorption of compounds such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG 200.
Liquids, particularly injectable compositions, may be prepared, for example, by dissolution, dispersion, and the like. For example, the disclosed compounds are dissolved in or mixed with a pharmaceutically acceptable solvent (e.g., water, saline, aqueous dextrose, glycerol, ethanol, and the like) to form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron, or serum proteins may be used to solubilize the disclosed compounds.
The disclosed compounds may also be formulated as suppositories, which may be prepared from fatty emulsions or suspensions; prepared using a polyalkylene glycol such as propylene glycol as the carrier.
The disclosed compounds may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids containing cholesterol, stearylamine or phosphatidylcholines. In some embodiments, the thin film of lipid component is hydrated with an aqueous drug solution to form a lipid layer encapsulating the drug, as described in U.S. patent No. 5,262,564, which is hereby incorporated by reference in its entirety.
The disclosed compounds can also be delivered by using monoclonal antibodies as separate carriers coupled to the disclosed compounds. The disclosed compounds can also be coupled to soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide polylysine substituted with palmitoyl residues. In addition, the disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels. In one embodiment, the disclosed compounds are not covalently bound to a polymer, such as a polycarboxylic acid polymer or polyacrylate.
Parenteral injection administration is commonly used for subcutaneous, intramuscular or intravenous injection and infusion. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, or as solid forms suitable for dissolution in liquid prior to injection.
Another aspect of the invention relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may also include excipients, diluents or surfactants.
The compositions may be prepared according to conventional mixing, granulating or coating methods, respectively, and the pharmaceutical compositions of the invention may contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20%, by weight or volume, of the disclosed compound.
The dosage regimen utilizing the disclosed compounds is selected in accordance with a variety of factors, including the type, species, age, weight, sex and physical condition of the patient; the severity of the condition to be treated; the route of administration; renal or hepatic function of the patient; and the particular disclosed compounds employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the pharmaceutically effective amount required to prevent, counter or arrest the progress of the condition.
When used for a given effect, an effective dose of the disclosed compounds, as required to treat the condition, ranges from about 0.5mg to about 5000mg of the disclosed compounds. Compositions for in vivo or in vitro use may contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500 or 5000mg of the disclosed compound, or, alternatively, in the range of one amount to another in a dosage list. In one embodiment, the composition is in the form of a tablet that may be scored.
Examples
The invention is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the scope or spirit of the invention to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments and are therefore not intended to limit the scope of the present disclosure. It is to be further understood that various other embodiments, modifications, and equivalents, which may occur to those skilled in the art, may be devised without departing from the spirit of the present disclosure and/or the scope of the appended claims.
Analytical methods, materials and apparatus
Reagents and solvents received from commercial suppliers were used as received unless otherwise indicated. Proton Nuclear Magnetic Resonance (NMR) spectra were obtained on a Bruker spectrometer at 400 MHz. The spectra are given in ppm (δ) and the coupling constants J are reported in hertz. Tetramethylsilane (TMS) was used as an internal standard. Mass spectra were collected using a Waters ZQ single quadrupole mass spectrometer (ion trap electrospray ionization (ESI)). Purity and low resolution mass spectral data were measured using a Waters Acquity i-class Ultra Performance Liquid Chromatography (UPLC) system with an Acquity photodiode array detector, an Acquity Evaporative Light Scattering Detector (ELSD) and a Waters ZQ mass spectrometer. Data were acquired using Waters MassLynx 4.1 software and purity was characterized by UV wavelength 220nm, evaporative Light Scattering Detection (ELSD) and electrospray ionization (ESI). (column: acquity UPLC BEH C18.7 μm 2.1x50mm; flow rate 0.6 mL/min; solvent A (95/5/0.1%: 10mM ammonium formate/acetonitrile/formic acid), solvent B (95/5/0.09%: acetonitrile/water/formic acid); gradient: 5-100% B from 0 to 2 minutes, 100% B to 2.2 minutes and 5%B at 2.21 minutes.
Abbreviations used in the following examples and elsewhere herein are:
ACN acetonitrile
br width
DCM dichloromethane
DIPEA N, N-diisopropylethylamine
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
EI electron ionization
ESI electrospray ionization
Et 2 O diethyl ether
EtOAc ethyl acetate
GCMS chromatography-mass spectrometry
h hours
HPLC high performance liquid chromatography
LCMS liquid chromatography-mass spectrometry
m multiplet
MeCN acetonitrile
MeOH methanol
MHz megahertz
min for
NMR nuclear magnetic resonance
Pd(PPh 3 ) 4 (triphenylphosphine) Palladium (0)
ppm parts per million
PSI PSI
s single peak
TBAF tetra-n-butylammonium fluoride
v volume
wt. wt
General method A for the Synthesis of Compounds of formula (I)
Figure GDA0003427688590000311
Example 1:2- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -N-methylacetamide (intermediate 1-5)
Figure GDA0003427688590000312
Step 1- ((4-bromo-2-nitrophenyl) amino) -N-methylacetamide (1-3)
To a solution of 4-bromo-1-fluoro-2-nitrobenzene (1-1, 1.10g, 4.55mmol) in 43mL of MeCN was added 2-amino-N-methylacetamide (1-2, 500mg, 5.69mmol). The mixture was stirred at 45 ℃ for 16 hours. The resulting precipitate was collected in a Buchner funnel, washed with DCM (3X 10 mL), then Et 2 O (3 × 10 mL) rinse afforded compound 2- ((4-bromo-2-nitrophenyl) amino) -N-methylacetamide 2-3 as a bright orange fluffy powder.
Step 2.2- ((2-amino-4-bromophenyl) amino) -N-methylacetamide (1-4)
A mixture of 2- ((4-bromo-2-nitrophenyl) amino) -N-methylacetamide (1-3, 932mg, 3.23mmol) and zinc (0) (1.68g, 25.84mmol) in acetone was stirred for about 1 minute, premixed NH was added 4 An aqueous solution of Cl (2.57g, 48.45mmol) and the resulting mixture was stirred at room temperature for 1 hour to give a colorless solution which was then concentrated in vacuo. The crude residue was extracted with DCM (3 × 100 mL) and the combined organic layers were dried over sodium sulfate, filtered through celite, and concentrated in vacuo to give compound 2- ((2-amino-4-bromophenyl) amino) -N-methylacetamide 1-4.
Step 3.2- (5-bromo-1H-benzo [ d ] imidazol-1-yl) -N-methylacetamide (1-5)
2- ((2-amino-4-bromophenyl) amino) -N-methylacetamide (1-4, 300mg, 1.16mmol) and trimethyl orthoformate (12 mL) were combined and stirred at 80 ℃ under argon for 24 h. The resulting mixture was concentrated in vacuo to afford a brown solid. Using the solid with Et 2 O (3X 10 mL) to give the compound 2- (5-bromo-1H-benzo [ d ] as a brown powder]Imidazol-1-yl) -N-methylacetamide 1-5.
Example 2: 5-bromo-1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazole (intermediate 2-2)
Figure GDA0003427688590000321
N- (4-bromo-2-nitrophenyl) -1-methyl-1H-pyrazol-4-amine (2-1, 6.85g, 23.14mmol) was combined with iron (Fe) (12.9g, 231.14mmol), ammonium chloride (12.9g, 231.14mmol), 20mL of formic acid (HCOOH), and 20mL of isopropanol. The mixture was stirred at 90 ℃ for 16 hours. The solid was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel, eluting with 0 to 15% MeOH/EtOAc, to give 5.1g of 5-bromo-1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazole 2-2 as a gray solid.
Example 3: 4-methyl-3- ((1- (2- (methylamino) -2-oxoethyl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-1)
Figure GDA0003427688590000331
Step 1.4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) -3 ((trimethylsilyl) ethynyl) benzamide (3-2)
3-iodo-4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (3-1, 5g, 12.3mmol) and Pd (PPh) 3 ) 4 (430mg, 0.37mmol) and CuI (120mg, 0.63mmol) were combined in a schlenk flask. The flask was placed under an inert atmosphere by evacuation and purged with N 2 The schlenk flask was backfilled. DIPEA (4.3mL, 24.6 mmol), ethynyltrimethylsilane (3.5mL, 24.6 mmol) and 25mL MeCN were then added. The resulting mixture was then stirred at 85 ℃ for 3 hours, cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel with 0 to 10% etoac/heptane to give 4.47g of 4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) -3- ((trimethylsilyl) ethynyl) benzamide 3-2 as a brown solid.
Step 2.4-methyl-3- ((1- (2- (methylamino) -2-oxoethyl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-1)
4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) -3- ((trimethylsilyl) ethynyl) benzamide (3-2, 150mg, 0.40mmol) was added to a TBAF solution (0.42 mL, 0.40mmol in 2mL THF in a microwave vial), and the resulting brown solution was stirred at room temperature for 10 minutes. The reaction mixture was concentrated using a stream of nitrogen to give an oil. Reacting 2- (5-bromo-1H-benzo [ d ]]Imidazol-1-yl) -N-methylacetamide (1-5, 71mg, 0.27mmol), pd (PPh) 3 ) 4 (9mg,0.0078mmol)、1mL iPr 2 NH and 4mL DMF were added to the vial and the mixture was stirred for 1 min. CuI (3 mg,0.016 mmol) was added, the vial was purged with argon and then heated to 100 ℃ in a microwave oven for 45 minutes. After cooling to room temperature, the reaction mixture was concentrated in vacuo and purified by flash column chromatography on silica gel (eluting with 0% to 15% meoh/EtOAc) to give the title compound (I-1) as a brown powder. The yield was 71%. 1 H-NMR(DMSO-d 6 )δ:11.31(s,1H),8.70(d,J＝5.0Hz,1H),8.55(s,1H),8.16-8.30(m,3H),7.96(dd,J＝7.9,2.0Hz,1H),7.91(d,J＝0.6Hz,1H),7.53-7.58(m,2H),7.46-7.52(m,2H),4.97(s,2H),2.66(d,J＝4.5Hz,3H),2.59(s,3H)。ESI-MS m/z:492.1[M+H] + 。
The following compounds in table 1 were prepared in a similar manner to example 3. Bromide intermediate 4c was purchased from a commercial source or synthesized as described in example 1 or 2. Intermediate 4d or its trans-amide analogues were prepared by standard amide formation methods as described in j.med.chem.2009,52,4743 and j.med.chem.2010,53,4701. For compound I-26, the starting aniline used was tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate A, shown below. For compound I-35 and compound I-43, the starting aniline used was 1-tosyl-1H-pyrazol-4-amine B shown below.
Table 1:
Figure GDA0003427688590000341
Figure GDA0003427688590000351
Figure GDA0003427688590000361
Figure GDA0003427688590000371
Figure GDA0003427688590000381
Figure GDA0003427688590000391
Figure GDA0003427688590000401
Figure GDA0003427688590000411
Figure GDA0003427688590000421
Figure GDA0003427688590000431
Figure GDA0003427688590000441
Figure GDA0003427688590000451
Figure GDA0003427688590000461
Figure GDA0003427688590000471
Figure GDA0003427688590000481
Figure GDA0003427688590000491
Figure GDA0003427688590000501
Figure GDA0003427688590000511
Figure GDA0003427688590000521
Figure GDA0003427688590000531
a the starting aniline is tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate A. b The starting aniline is 1-tosyl-1H-pyrazol-4-amine B. A and B are as follows:
Figure GDA0003427688590000541
biochemical assay
Example 2: c-Kit assay
Engineering cell lines to generate Ba/F3 KIT mutants
KIT cDNA was synthesized by GenScript and cloned into pLVX-IRES-Puro vector (Clontech). Viral particles were generated by transfecting the pLVX-IRES-puro vector containing the KIT mutant gene into HEK293 cells (Invitrogen) using a trans lentiviral ORF packaging KIT (Thermo Scientific). At 48 hours post-transfection, virus-containing supernatants were harvested and incubated with parental Ba/F3 cells (DSMZ) in the presence of 10ng/mL IL-3 (R & D Systems) for an additional 48-72 hours. Transduced Ba/F3 cells were then selected by IL-3 withdrawal and puromycin (0.5-1. Mu.g/mL, invitrogen).
Determination of viability
The cell lines (i.e., EX11DEL/D816H, EX DEL/T670I and EX11 DEL/V654A) were seeded into 384-well plates at a density that produces linear growth using RPMI 1640 supplemented with 10-percent FBS and incubated in 5% (V/V) CO2 at 37 ℃. Cells were treated with eight concentrations of compound at 4-fold dilutions (10 μ M to 0.61 nM) and viability was assessed after 72 hours using the Cell Titer-Glo assay (Promega). Data are plotted as percent viability relative to vehicle-treated cells. Dose-response curves were generated and used to calculate IC 50 The value is obtained.
Table 2: c-Kit activity of the compounds of the invention in a c-Kit assay. + + + + + + + + + + -denotes IC 50 Less than about 10nM, + ++ denotes IC 50 Between about 10nM and about 50nM, with ++ representing IC 50 Between about 50nM and about 100nM, and + represents IC 50 Greater than about 100nM and less than about 10. Mu.M.
Table 2: cKit assay
Figure GDA0003427688590000542
Figure GDA0003427688590000551
Figure GDA0003427688590000561
Equivalent scheme
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed by the scope of the following claims.

Claims (26)

1. A compound of formula (Ii) or (Ij):
Figure FDA0003777415070000011
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is H;
R 2 is H, (C) 1 -C 6 ) Alkyl, - (C (R) 6a ) 2 ) p -(C 3 -C 7 ) Cycloalkyl, - (C (R) 6a ) 2 ) p -heterocycloalkyl, wherein said heterocycloalkyl comprises 4 to 7 membered rings and 1 to 3 heteroatoms selected from N, O and S, - (C (R) 6a ) 2 ) p -(C 6 -C 10 ) Aryl or- (C (R) 6a ) 2 ) p -heteroaryl, wherein said heteroaryl comprises a 5 or 6 membered ring and 1 to 3 heteroatoms selected from N, O and S, wherein said aryl is interrupted by one or more R 7 Optionally substituted, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted with one or more R 9 Optionally substituted;
each R 3 Independently at each occurrence is (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkoxy group, (C) 1 -C 6 ) Haloalkyl, (C) 1 -C 6 ) Haloalkoxy, halogen or OH;
each R 4 Independently at each occurrence is (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkoxy group, (C) 1 -C 6 ) Haloalkyl, (C) 1 -C 6 ) Haloalkoxy, halogen, -OH, CN, (C) 3 -C 7 ) Cycloalkyl, - (C (R) 6b ) 2 ) q -NH 2 、-(C(R 6b ) 2 ) q -(C 1 -C 6 ) Alkylamino, - (C (R) 6b ) 2 ) q -(C 1 -C 6 ) Dialkylamino, - (C (R) 6b ) 2 ) q -heterocycloalkyl, wherein said heterocycloalkyl comprises 4 to 7 membered rings and 1 to 3 heteroatoms selected from N, O and S,or- (C (R) 6b ) 2 ) q -heteroaryl, wherein said heteroaryl comprises a 5 or 6 membered ring and 1 to 3 heteroatoms selected from N, O and S, and wherein said heterocycloalkyl or said heteroaryl is optionally substituted with one or more substituents each independently selected from (C) 1 -C 6 ) Alkyl, -NH 2 、(C 1 -C 6 ) Alkylamino and (C) 1 -C 6 ) A dialkylamino group;
R 5 is H, (C) 1 -C 6 ) Alkyl or (C) 1 -C 6 ) A haloalkyl group;
each R 6a And R 6b Independently is H or (C) 1 -C 6 ) An alkyl group;
R 7 is (C) 1 -C 6 ) Alkoxy group, (C) 1 -C 6 ) Haloalkoxy, -OH, -NH 2 、(C 1 -C 6 ) Alkylamino radical, (C) 1 -C 6 ) Dialkylamino or-C (O) N (R) 8 ) 2 ；
Each R 8 Independently H, (C) 1 -C 6 ) Alkyl or (C) 1 -C 6 ) A haloalkyl group;
each R 9 Independently at each occurrence is (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Haloalkyl, -C (O) H, -C (O) (C) 1 -C 6 ) An alkyl or 5 to 7 membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from N, O and S, wherein said heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C) 1 -C 6 ) Alkyl, -C (O) H or
-C(O)(C 1 -C 6 ) And wherein said aryl is optionally substituted with one or more substituents each independently selected from (C) 1 -C 6 ) Alkoxy, -OH, (C) 1 -C 6 ) Haloalkoxy, -NH 2 、(C 1 -C 6 ) Alkylamino or (C) 1 -C 6 ) A dialkylamino group; and is
Each n, p and q is independently 0, 1 or 2.
2. The compound of claim 1, having the following formula (Ii):
Figure FDA0003777415070000021
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1, having the following formula (Ij):
Figure FDA0003777415070000022
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1, wherein R 5 Is H.
5. The compound of claim 1, wherein R 4 Is (C) 1 -C 6 ) A haloalkyl group.
6. The compound of claim 1, wherein R 4 Is CF 3 。
7. The compound of claim 1, wherein n is 1,R 3 Is methyl, and R 2 Is H; CH (CH) 3 ；CH 2 CH 3 ；-(CH 2 ) 2 N(CH 3 ) 2 ；-(CH 2 ) 3 N(CH 3 ) 2 ；-CH 2 C(O)NH(CH 3 )；-(CH 2 ) 2 Morpholinyl; - (CH) 2 ) 2 OCH 3 (ii) a Piperidinyl substituted with methyl; phenyl optionally substituted with 4-methylpiperazine; -CH 2 -a pyridyl group; a cyclopropyl group; a methyl-substituted triazolyl group; or imidazolyl substituted with methyl or N-methylpiperidinyl.
8. The compound of claim 1, wherein n is 1 and R 3 Is methyl, R 2 Is pyrazolyl optionally substituted with methyl; - (CH) 2 ) 2 OH；-(CH 2 ) 2 OCH 3 ；-(CH 2 ) 2 N(CH 3 ) 2 ；-(CH 2 ) 2 N(CH 2 CH 3 ) 2 (ii) a Morpholinyl; or piperidinyl optionally substituted with methyl or-C (O) H.
9. The compound of claim 1, wherein n is 0 or 1 and R 3 Is F, R 2 Is pyrazolyl optionally substituted by methyl.
10. A compound selected from the group consisting of:
4-methyl-3- ((1- (2- (methylamino) -2-oxoethyl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
3- ((1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
3- ((1- (2- (dimethylamino) ethyl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
3- ((1- (2-methoxyethyl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
4-methyl-3- ((1- (2-morpholinoethyl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
3- ((1- (3- (dimethylamino) propyl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
3- ((1-ethyl-1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
4-methyl-3- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
3- ((2-amino-1H-benzo [ d ] imidazol-6-yl) ethynyl) -4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
4-methyl-3- ((1-methyl-1H-benzo [ d ] imidazol-6-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
4-methyl-3- ((1- (pyridin-3-ylmethyl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
3- ((1-cyclopropyl-1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
4-methyl-3- ((1- (3- (4-methylpiperazin-1-yl) phenyl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
4-methyl-3- ((1- (4- (4-methylpiperazin-1-yl) phenyl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
4-methyl-3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
n- (4-methyl-3- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) ethynyl) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) benzamide;
4-methyl-3- ((1- (1-methylpiperidin-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
4-methyl-3- ((1-phenyl-1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
4-methyl-3- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) benzamide;
4-methyl-3- ((1- (1-methyl-1H-imidazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
4-methyl-3- ((1- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
3- ((1- (1- (1-formylpiperidin-4-yl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
4-methyl-3- ((1- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
4-methyl-3- ((1- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
n- (3-cyclopropylphenyl) -4-methyl-3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) benzamide;
4-methyl-3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (pyrrolidin-1-ylmethyl) -3- (trifluoromethyl) phenyl) benzamide;
4-methyl-3- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (pyrrolidin-1-ylmethyl) -3- (trifluoromethyl) phenyl) benzamide;
3- ((1- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
3- ((1- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
4-methyl-3- ((1- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
4-methyl-3- ((1- (1- (1-methylpiperidin-4-yl) -1H-imidazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
3- ((1- (1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
n- (4-methyl-3- ((1- (1-methyl-1H-1,2,3-triazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) phenyl) -4- (trifluoromethyl) picolinamide;
n- (4-cyano-3- (trifluoromethyl) phenyl) -4-methyl-3- ((1- (1-methyl-1H-pyrazol-3-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) benzamide;
n- (3- ((1- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methylphenyl) -4- (trifluoromethyl) picolinamide;
n- (3- ((1- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methylphenyl) -4- (trifluoromethyl) picolinamide;
n- (3- ((1- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methylphenyl) -4- (trifluoromethyl) picolinamide;
n- (3- ((1- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methylphenyl) -4- (trifluoromethyl) picolinamide;
n- (3- ((1- (1- (2- (diethylamino) ethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methylphenyl) -4- (trifluoromethyl) picolinamide;
n- (3- ((1- (1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -4-methylphenyl) -4- (trifluoromethyl) picolinamide;
n- (4-methyl-3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) phenyl) -4- (trifluoromethyl) picolinamide;
n- (4-methyl-3- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) ethynyl) phenyl) -4- (trifluoromethyl) picolinamide;
n- (4-methyl-3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) benzamide;
n- (4-methyl-3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) phenyl) -4- (pyrrolidin-1-ylmethyl) -3- (trifluoromethyl) benzamide;
n- (4-methyl-3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) phenyl) -4- (morpholinomethyl) -3- (trifluoromethyl) benzamide;
n- (3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) phenyl) -4- (trifluoromethyl) picolinamide;
3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
4-fluoro-3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide; and
n- (4-fluoro-3- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-5-yl) ethynyl) phenyl) -4- (trifluoromethyl) picolinamide;
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1, wherein:
R 2 is- (C (R) 6a ) 2 ) p -heteroaryl, wherein said heteroaryl comprises a 5 or 6 membered ring and 1 to 3 heteroatoms selected from N, O and S, wherein said heteroaryl is interrupted by one or more R 9 Optionally substituted;
R 3 is (C) 1 -C 6 ) Alkyl or halogen;
R 4 is (C) 1 -C 6 ) A halogenated alkyl group,
R 5 is H;
each R 9 Independently at each occurrence is (C) 1 -C 6 ) An alkyl or 5 to 7 membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from N, O and S, wherein said heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C) 1 -C 6 ) Alkyl or-C (O) H, and wherein the alkyl is optionally substituted with one or more substituents each independently selected from (C) 1 -C 6 ) Alkoxy, -OH or (C) 1 -C 6 ) A dialkylamino group;
p is 0; and is
n is 0, 1 or 2.
12. The compound of claim 11, wherein R 4 Is CF 3 。
13. The compound of claim 11, wherein n is 1,R 3 Is methyl, R 2 Is a methyl-substituted triazolyl group, or is a methyl-or N-methylpiperidyl-substituted imidazolyl group.
14. The compound of claim 11, wherein n is 1,R 3 Is methyl, R 2 Is pyrazolyl optionally substituted by methyl, - (CH) 2 ) 2 OH、-(CH 2 ) 2 OCH 3 、-(CH 2 ) 2 N(CH 3 ) 2 、-(CH 2 ) 2 N(CH 2 CH 3 ) 2 Tetrahydropyranyl, or piperidinyl optionally substituted with methyl or-C (O) H.
15. The compound of claim 11, having the formula:
Figure FDA0003777415070000061
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 15, wherein R 4 Is CF 3 。
17. The compound of claim 15, wherein n is 1,R 3 Is methyl, R 2 Is a methyl-substituted triazolyl group, or is a methyl-or N-methylpiperidyl-substituted imidazolyl group.
18. The compound of claim 15, wherein n is 1,R 3 Is methyl, R 2 Is pyrazolyl optionally substituted by methyl, - (CH) 2 ) 2 OH、-(CH 2 ) 2 OCH 3 、-(CH 2 ) 2 N(CH 3 ) 2 、-(CH 2 ) 2 N(CH 2 CH 3 ) 2 Tetrahydropyranyl, or piperidinyl optionally substituted with methyl or-C (O) H.
19. The compound of claim 11, having the formula:
Figure FDA0003777415070000071
or a pharmaceutically acceptable salt thereof.
20. The compound of claim 19, wherein R 4 Is CF 3 。
21. The compound of claim 19, wherein n is 1,R 3 Is methyl, R 2 Is a methyl-substituted triazolyl group, or is a methyl-or N-methylpiperidyl-substituted imidazolyl group.
22. The compound of claim 19, wherein n is 1,R 3 Is methyl, R 2 Is pyrazolyl optionally substituted by methyl, - (CH) 2 ) 2 OH、-(CH 2 ) 2 OCH 3 、-(CH 2 ) 2 N(CH 3 ) 2 、-(CH 2 ) 2 N(CH 2 CH 3 ) 2 Tetrahydropyranyl, or piperidinyl optionally substituted with methyl or-C (O) H.
23. A pharmaceutical composition comprising a compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, excipient or carrier.
24. Use of a compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a c-Kit mediated disease or disorder, wherein the c-Kit mediated disease or disorder is selected from a cell proliferative disorder, a fibrotic disorder, a metabolic disorder, multiple sclerosis, asthma, an allergic response, inflammatory arthritis, or mastocytosis.
25. The use of claim 24, wherein the cell proliferative disorder is cancer, optionally wherein the cancer is selected from:
leukemia, mast cell tumor, small cell lung cancer, testicular cancer, gastrointestinal cancer, central nervous system cancer, female genital tract cancer, sarcoma of neuroectodermal origin, and schwann cell tumor associated with neurofibromatosis; or the cancer is selected from:
acute Myeloid Leukemia (AML), neuroblastoma, malignant melanoma, colorectal cancer, systemic Mastocytosis (SM), and gastrointestinal stromal tumor (GIST).
26. Use of a compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a c-Kit mediated disease or condition, wherein the c-Kit mediated disease or condition is multiple sclerosis, asthma, anaphylaxis, inflammatory arthritis, or mastocytosis.
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